Drug delivery systems and methods

ABSTRACT

The present invention relates to a drug delivery device for mixing and delivering a drug by injection. The device includes a housing having a first port or opening therein that receives a first container that contains a fluid or powdered drug, for example a lyophilized drug. The housing can also include a second port or opening that receives a second container that contains a fluid to be mixed with the drug to form an injectable fluid. The device includes a manifold having a channel that fluidly connects the first and second containers. A penetrating membrane such as a needle is used to inject the drug into a patient which is in fluid communication with the first container. The needle is movable from a storage position in the housing to an injection position extending through the housing.

RELATED APPLICATIONS

[0001] This application is a Divisional application of, and claimspriority under 35 U.S.C. §121 to, A. Ser. No. 09/439,725 entitled DRUGDELIVERY SYSTEMS & METHODS, filed on Nov. 12, 1999, which in turn claimspriority under 35 U.S.C. §119(e) to Provisional application A. S. No.60/108,382 filed on Nov. 13, 1998 and to Provisional application A. S.No. 60/131,644 filed on Apr. 29, 1999.

BACKGROUND OF THE INVENTION

[0002] The present invention relates to the preparation andadministration of a product and, more particularly, to the injection ofthe same into a living organism, for example, a human body.

[0003] Previously, various devices have been developed for thepercutaneous delivery of medications into living organisms includingsyringes in which a liquid is delivered from a chamber using pressureasserted by a manual plunger through a needle inserted under the skin.

[0004] Additionally, it is well known in the art that the storage lifeof certain injectable substances such as glucagon, used to dissolveblood clots, is increased when the substance is stored in a powdered orlyophilized state, for example. These lyophilized substances (i.e.,drugs or compounds) are presently used for injection of materials thatwould otherwise be unstable. Lyophilization, for example, is the rapidfreezing of a material at a very low temperature followed by rapiddehydration by sublimation in a high vacuum. The resulting lyophilizedcompound is typically stored in a glass vial or cartridge which isclosed by a cap, such as a rubber stopper or septum.

[0005] It is necessary to reconstitute the powdered or solid material,such as a lyophilized compound, prior to administration. This isaccomplished by mixing the solid compound with a suitable diluent orliquid. Reconstitution typically involves the use of a syringe with aneedle to withdraw the diluent from a separate vial and inject it intothe vial containing the compound. The compound is then thoroughly mixed,typically by shaking the vial by hand, and a separate syringe with aneedle withdraws the desired amount to be injected into the patient.Because two separate containers are used, the person reconstituting thecompound must be certain to mix the correct amounts such that a properconcentration of the mixture results. When a syringe is used to mix thediluent and drug, the exact volume of diluent to drug ratio is difficultto obtain. Thus, precise concentration levels of administered drug maybe compromised.

[0006] Moreover, because the diluent and compound are in separatesterilized containers, the manual withdrawal of diluent via a syringeand reinjection of the same into the container containing the solidmaterial such as a powdered or lyophilized drug may compromisesterility, and safety due to the use of a syringe.

[0007] Because of increased use of powdered compounds or lyophilizeddrugs, for example, it is desirable to provide both professional andnon-professional personnel with a reconstituted drug delivery system. Itis desirable to have a simple, reliable system that facilitatespreparation and safe delivery of an accurate dosage of a reconstitutedcompound. In addition, it is desirable to provide a system thatreconstitutes a lyophilized drug while maintaining sterility throughoutthe process. Also, it is desirable to provide improvements in thepercutaneous delivery of medication generally, which provide for safe,effective administration by the user.

SUMMARY OF THE INVENTION

[0008] The present invention relates to systems and methods fordelivering liquid drugs to a user. The drug delivery system can includedelivery of reconstituted powdered drugs such as, for example,lyophilized drugs, or more generally for the transfer and delivery ofliquid drugs. Powdered or lyophilized drug delivery further includes asystem to reconstitute the powdered drug. The drug delivery systems mayfurther include a pressurization system which pressurizes the drug fortransfer to a delivery system or for direct subcutaneous delivery.Further, the drug delivery system in accordance with the presentinvention includes an injector system which contacts the tissue anddelivers the drug to the patient or user. In the alternative, the drugdelivery system in accordance with the present invention includesfilling of detachable delivery devices, for example, a standard syringe,a needleless injector, an infusion device or different types of pumps.Another example uses a pen injector which aspirates the liquid drug fromthe system and in turn delivers the drug subcutaneously.

[0009] The methods for delivering a powdered drug such as a lyophilizeddrug include the steps of pressurizing a diluent solution in a diluentvial. The pressurizing systems may include, but are not limited to, acompressed air supply, a chemical gas generator, a collapsible volumesupply, a bellow canister, a standard syringe or a cylinder, forexample. The methods further include the step of delivering thepressurized diluent solution to the powdered drug vial. The next step inthe method includes the reconstitution of the drug to form a liquid drugby mixing the powdered drug with the diluent solution. The methodsfurther include the steps of providing the liquid drug to an injectorsystem or transferring the liquid drug to detachable delivery devices.The following step includes the injection of the liquid drug into thetissue of the patient or user. The methods further include the steps ofmoving the injection needle from a delivery or injection position to aretracted or storage position once delivery is complete. It should benoted that, depending on the application or delivery of differentmedicaments, the features of the drug delivery systems may vary. Forexample, the pressurization level can vary depending upon the viscositylevel of the medicament, and the needle type or length can varydepending upon subcutaneous injection or intermuscular injection. Forexample, for subcutaneous injections, the needle length ranges from 5 to12 mm while the needle length may vary up to about 3 cm forintermuscular injections.

[0010] The methods for delivering a liquid medicament to a patientinclude the steps of pressurizing the liquid drug solution in the vialwith a pressurizing system. The subsequent steps are similar to thesteps described with respect to the methods for delivering a powderedmedicament.

[0011] A preferred embodiment of the present invention features aninjector system having an angled or unshaped needle. Another preferredembodiment of the present invention features an injector system having astraight needle. Yet another preferred embodiment of the presentinvention employs a transfer system for transferring the drug todelivery devices such as, for example, a standard syringe with a needleor a needleless pen injector. The devices receive the liquid drug from acontainer, such as a vial containing the liquid drug. The deliverydevices subsequently deliver the medication to the user's tissue asdescribed herein.

[0012] Another preferred embodiment of the present invention features acombination system having the ability to reconstitute drug into solutionand subsequently inject it into a user in accordance with thisembodiment the reconstituted drug delivery system has a housing having afirst opening or port that receives a first container that contains asolid substance, such as a powdered lyophilized drug, for injection. Itshould be noted that the container is a rigid container, such as, forexample, a vial or a cartridge containing the powdered drug. The housingcan also include a second opening or port that receives a secondcontainer that contains a fluid to be mixed with material in the firstcontainer, to form an injectable fluid. The drug delivery system mayinclude a manifold having a first channel that provides fluidcommunication between the first and second containers. The manifoldfurther includes a second channel between the first container and adelivery or transfer device. The manifold can also include acommunication channel to a pressurization system which provides thedriving pressure to deliver the liquid drug. In a preferred embodiment,the penetrating member is a needle, in fluid communication with thefirst container after the needle moves between a storage position in thehousing to an injection position extending outside the housing and intothe user.

[0013] A preferred embodiment of the invention provides for concealmentof the injection needle within the main housing of the drug deliverydevice except during the injection of the drug to the user. Thisembodiment can include a needle retraction device for withdrawing theneedle into the housing after injection to minimize the risk of exposureto a contaminated needle.

[0014] In accordance with other aspects of the present invention, thelength of the delivery path from the container with the injectable fluidto the injection needle is reduced to minimize loss of residual amountof liquid drug. According to another aspect of the invention, theinjection needle first pierces the skin of the person being injected andis concurrently placed in fluid communication with the first containerthat contains the injectable fluid. According to yet another aspect ofthe invention, the container that contains the injectable fluid issubstantially visible during reconstitution and injection such that theuser can visually observe the process. A compressed fluid, such as a gasin the container with the injectable fluid, is used to force theinjectable liquid through the injection needle and into the tissue beinginjected. In an alternative embodiment, the device has a single portwith a compression element such that a container with a liquidmedication, such as a previously reconstituted material, can be insertedinto the housing and simultaneously pressurized to the needed pressureto deliver the correct dose over a predetermined time period.

[0015] In a preferred embodiment of the system, the device is used withthe injectable fluid container being vertically oriented duringinjection. To reduce the risk of injecting any gas into the injectionsite, a gas impermeable membrane such as a hydrophilic membrane isdisposed in the fluid path, which in a wetted state minimizes orpreferably prevents gas flow while allowing liquid to flow through themembrane. The rigid containers need to be in a vertical orientationduring reconstitution for appropriate pressurization. In an embodimentincluding a cartridge having diluent and air, a vertical orientation isnot required for reconstitution. According to a further aspect of thepresent invention, the axis of the injection needle is perpendicular tothe longitudinal axis of the container with the injectable fluid. In apreferred embodiment, the containers containing a powdered orlyophilized drug and diluent are inserted in the housing in the samedirection along parallel axes. In another embodiment, the containers areinserted along a common axis or parallel axes in the opposite direction.The system can have housing apertures, ports, or openings that have asize compatible with standard vial and cartridge sizes such thatexisting vials and/or cartridges can be used. The container contents donot have to be mixed until immediately prior to injection. Because thecontents of the containers are only in contact with other sterile parts,sterility prior to and during the reconstitution process is maintained.

[0016] According to another aspect of the present invention a furtherimprovement to reduce and preferably prevent the risk of injecting gasinto the injection site, includes the use of a drug which is gasimpermeable once wetted. Further, since the gas impermeable membrane cansustain pressure, the delivery time for the liquid drugs is shortened asa higher driving force is generated using pressurization systems. Bydisposing such a membrane such as a hydrophilic membrane in the drugdelivery path that is gas impermeable in a wetted state, gas needed tocontrol injection pressure and duration can be added in the system asthe membrane checks the delivery of gas to the user. The containercontaining the fluid can be a changeable volume container which containsa controllable volume of a gas, for example, air. This controllablevolume of air and/or fluid are forced into the drug container, resultingin a drug under pressure to deliver the correct dose over a selectedtime period. According to a further aspect of the invention, the deviceincludes a manifold system to minimize the drug delivery path andsimplify assembly costs, and increase system reliability. The simplicityand flexibility of the manifold system facilitates the use of standardprefilled cartridges and syringes. In a preferred embodiment, themanifold is a two-piece polycarbonate molding in which the two moldedelements are ultrasonically welded together. The gas impermeablemembrane is attached or welded to one piece of the polycarbonatemolding.

[0017] According to another aspect of the present invention, a furtherimprovement to deliver an accurate predicted volume of a drug includesadjustable height penetrating members, such as, for example, outletspikes. In the alternative, delivery of an accurate predicted volume,for example 50% or 80% etc., can be gauged from the residual drug volumeor the use of detachable delivery devices, for example, a standardsyringe or a pen-type pump injector.

[0018] According to another aspect of the present invention, a furtherimprovement to the drug delivery systems includes interlocks andindicators which ensure the safe and accurate delivery of the drugs. Theinterlocks include, but are not limited to latches which provide for adesired sequence of operation such as pressurization of containers tofollow the step of insertion of the containers, or prevention ofdisplacement of the needle to an injection position after a firstinjection use. The indicators include a vertical orientation indicatorand end of delivery indicators.

[0019] According to another aspect of the present invention, the housingof the drug delivery device is shaped and designed to functionappropriately to enable single handed operation. For example, the bottomsurface of the housing is flat in shape to allow table top placement toaccommodate single handed operation by the user. Further, the device issized to enable the insertion of vials and subsequent activation of thedevice using one hand.

[0020] In a preferred embodiment, the system housing is lightweight andcompact, having a weight of less than 30 grams and a volume of less than100 cm³. This provides a portable disposable device that can bediscarded or recycled after a single use and that is readily transportedby the user. In addition, the present invention is self-contained andmaintains sterility throughout the reconstitution and injection of afluid such as a lyophilized drug. It should be noted, the weight andvolume of the system housing can vary depending upon the differentembodiments and the volume of drug being delivered to a user.

BRIEF DESCRIPTION OF THE DRAWINGS

[0021] FIGS. 1A-1F illustrate the operation of a preferred embodiment ofa drug delivery device in accordance with the present invention.

[0022]FIGS. 2A and 2B illustrate cutaway views of the drug deliverydevice shown in FIGS. 1A-1F, along line 2A, 2B-2A, 2B in FIG. 1F.

[0023] FIGS. 3A-3D illustrate the sectional views of the internalcomponents of the drug delivery device of FIGS. 1A-1E and FIG. 2 duringadministration of the reconstituted drug.

[0024] FIGS. 4A-4O illustrate the operation of a preferred embodiment ofa drug delivery device in accordance with the present invention.

[0025] FIGS. 5A-5C are perspective views of a preferred embodiment of adrug delivery device in accordance with the present invention.

[0026] FIGS. 6A-6C illustrate the operation of a drug delivery devicesubstantially similar to the device shown in FIGS. 5A-5C.

[0027] FIGS. 7A-7C are partial perspective views of the drug deliverydevice of FIGS. 5A-5C and 6A-6C illustrating the injection of the drug.

[0028] FIGS. 8A-8F illustrate the operation of a drug delivery devicesubstantially similar to the device shown in FIGS. 5A-5C.

[0029] FIGS. 9A-9F illustrate the operation of a preferred embodiment ofa drug delivery device in accordance with the present invention.

[0030]FIGS. 10A and 10B are graphical illustrations of the pressure,weight, and delivery characteristics of a preferred embodiment of theinvention.

[0031] FIGS. 11A-11D illustrate cutaway views of an alternativeembodiment including a drug container subassembly of the drug deliverydevice in accordance with the present invention.

[0032] FIGS. 12A-12B illustrate perspective views of a preferredembodiment of the diluent container subassembly shown in FIGS. 11A-11D.

[0033]FIGS. 13A and 13B illustrate cutaway views of an alternateembodiment of the drug delivery device in accordance with the presentinvention.

[0034]FIG. 14 illustrates a cutaway view of another preferred embodimentof the drug delivery device in accordance with the present invention.

[0035]FIGS. 15A and 15D illustrate cutaway views of an alternateembodiment of the drug delivery device in accordance with the presentinvention.

[0036]FIG. 16 illustrates a cutaway view of an injection device inaccordance with the present invention.

[0037] FIGS. 17A-17C illustrate cutaway views of an alternate embodimentof the drug delivery device in accordance with the present invention.

[0038] FIGS. 18A-18C illustrate cutaway views of an alternate embodimentof the injector system of the drug delivery system in accordance withthe present invention.

[0039] FIGS. 19A-19F illustrate alternate embodiments of pressurizationsystems included in the drug transfer system in accordance with thepresent transfer invention.

[0040] FIGS. 20A-20C illustrate views of an alternate embodiment of the(Hug delivery system in accordance with the present invention which usesstandard vials containing a liquid medicament.

[0041]FIG. 21 illustrates a view of another preferred embodiment of thedrug delivery system in accordance with the present invention which usesstandard vials containing a liquid medicament.

[0042] FIGS. 22A-22E illustrate cutaway and perspective views of analternate embodiment of the drug delivery system in accordance with thepresent invention.

[0043]FIGS. 23A and 23B illustrate alternate preferred embodiments tocontrol the dose of drugs in accordance with the present invention.

[0044] FIGS. 24A-24C illustrate cutaway views of an alternate embodimentof the drug delivery system in accordance with the present inventionincorporating filling devices, for example a syringe, to inject the drugsystem.

[0045]FIG. 25 illustrates a cutaway view of an alternate embodiment ofthe drug transfer system in accordance with the present inventionincorporating filling devices, for example a pen type pump to inject theliquid medicament.

[0046] FIGS. 26A-26D illustrate perspective views of a preferredembodiment of a drug transfer system in accordance with the presentinvention.

[0047] FIGS. 27A-27C illustrate cutaway views of a preferred embodimentof a drug delivery system in accordance with the present invention.

[0048] FIGS. 28A-28C illustrate cutaway views of the operation of apreferred embodiment of a drug delivery system in accordance with thepresent invention.

[0049]FIG. 28D illustrates an enlarged cutaway view of a preferredembodiment of the spike which brings the liquid drug in communicationwith the delivery system in FIGS. 28A-28C.

[0050]FIGS. 29A and 29B illustrate partial cutaway views of a preferredembodiment of the drug transfer delivery system in accordance with thepresent invention.

[0051]FIGS. 30A and 30B are views showing the two piece construction ofthe manifold in accordance with the drug delivery system of the presentinvention.

[0052] FIGS. 31A-31G are perspective views of a preferred embodiment ofa drug delivery system in accordance with the present invention.

[0053] FIGS. 32A-32E are perspective views of another preferredembodiment of a drug delivery system in accordance with the presentinvention.

[0054] FIGS. 33A-33I are cutaway views illustrating the interlocks builtinto the drug delivery system in accordance with the present invention.

[0055] FIGS. 34A-34D are views of a preferred embodiment illustrating anend of delivery indicator of the drug delivery system in accordance withthe present invention.

[0056]FIG. 35 is a graphical illustration of a delivery profile of apreferred embodiment of the drug delivery system with no additionalvolume of air in the liquid vial in accordance with the presentinvention.

[0057]FIG. 36 is a graphical illustration of the delivery duration anddelivery pressure of a preferred embodiment of the drug delivery systemin accordance with the present invention.

[0058]FIG. 37 is a graphical illustration of delivery parameters ofinjecting a drug with no additional volume of air in accordance with thepresent invention.

[0059]FIG. 38 is a graphical illustration of the air pressure gradienton a hydrophilic membrane in the drug delivery system in accordance withthe present invention.

[0060]FIG. 39 is a graphical illustration of the delivery profile withrespect to time for a vial system containing about 7.5 ml of air inaccordance with the present invention.

[0061]FIG. 40 is a flowchart describing the method of delivery of areconstituted drug in accordance with the present invention.

[0062]FIG. 41 is a flowchart describing the method of delivery of aliquid drug in accordance with the present invention.

[0063] The foregoing and other objects, features, and advantages of thedrug delivery systems and methods will be apparent from the followingmore particular description of preferred embodiments of the invention,as illustrated in the accompanying drawings in which like referencecharacters refer to the same parts throughout the different views. Thedrawings are not necessarily to scale, emphasis instead being placedupon illustrating the principles of the invention.

DETAILED DESCRIPTION OF THE INVENTION

[0064] The present invention is directed to drug delivery system is andmethods. The drug delivery system provides generally for the delivery ofa drug in solution under pressure, and more particularly to theinjection of powdered or lyophilized drugs that require reconstitution.The drug delivery system includes a reconstitution system, apressurization system to facilitate drug delivery, a transfer system andan injector system. Different embodiments of the present invention mayuse only one of the systems described and other embodiments can employcombination of these systems, depending on the requirements of differentapplications. For example, a preferred embodiment can deliver a liquiddrug and not require reconstitution. Therefore the drug delivery systemsand methods are a combination of some or all of the systems or processesdescribed below.

[0065] With reference to FIGS. 1A-1E, the general operation of apreferred embodiment of a drug delivery device 100 is illustrated. FIGS.2A-2B, and 3A-3D provide sectional views of the same embodiment forclarity. As specifically illustrated in FIG. 1A, drug delivery device100 comprises a first member or housing 304 and a pivotally connectedsecond member or handle 106. The device 100 is used to mix, within asterilized environment, a first liquid such as a diluent 166 (forexample, a fluid such as sterilized water) with a second powdered drugsuch as a lyophilized drug or compound concentrate 164, e.g.,interferon, and to inject the resulting reconstituted lyophilized druginto a living organism, which in the preferred embodiment is a humanbeing. Advantageously, the device 100 utilizes a standard vial or firststorage container 102, which contains the lyophilized drug or compound164, and a standard cartridge or second storage container 116, whichcontains the diluent 166. The device 100 may be formed from inexpensivematerials, such as plastic or the like, such that it is economicallyfeasible to dispose of the device after a single injection.

[0066] In preparation for the administration of the drug, the userremoves protective packaging which envelops the device 100. Thispackaging maintains sterility of the device 100 prior to use. In thepreferred embodiment of the invention, cartridge 116 containing diluent166 comes preassembled, being locked into the bottom of housing 304 bythe arms 133 as shown in FIGS. 2A and 2B.

[0067] The sterility protector of the vial 102 is removed and thenlocked into the top of housing 304 as shown in FIG. 2A with a needle 124from the housing penetrating a stopper 112 of the vial. At this stage,vial 102 is filled with air at ambient pressure. The cartridge 116 ispushed upward, i.e., toward vial 102. The cartridge 116 is punctured andthe diluent 166 is delivered to the vial 102 as shown in part in FIG.1C. At this stage, as will be explained below, there is a fluid such asgas in vial 102 which is compressed by transfer of diluent 166 into vial102. The user swills the device 100 to ensure the lyophilized drug isappropriately reconstituted. The reconstituted lyophilized drug, orinjectable fluid, is identified as reference number 160.

[0068] Now, drug in solution with the diluent is ready for injection.The device 100 is pressed against the skin of the person to be injectedwith the vial 102 in a vertical orientation to ensure that thecompressed gas, for example, air is used to inject the reconstituteddrug and that the gas or air is not injected into the injection site.The user presses the handle 106 which causes the injection needle 130 tomove between a first position, or storage position, within the housing304 as shown in FIG. 3A, and a second position, or injection position,outside the housing as shown in FIG. 3C. It is preferred that the needleextend out of the housing 304 in the range of 5 to 12 millimeters. Thesecond extended position of the injection needle 130 is also illustratedin FIG. 1D. At this point, the injection needle 130 is fluidly connectedto vial 102 such that the reconstituted lyophilized drug 160, underpressure from the compressed gas in vial 102, is delivered to theinjection site. The delivery of the reconstituted lyophilized drug 160can be completed in a time period in the range of 10-30 seconds.

[0069] Upon release of handle 106, a biasing mechanism 108 (to bedetailed below) returns the handle to the original position.Simultaneously, a needle retraction mechanism (also to be describedbelow) locks the injection needle 130 within the housing 304, therebyreducing and preferably preventing exposure of the contaminated needle.The final stage of operation is illustrated in FIG. 1E, wherein thedevice 100 may be safely discarded.

[0070]FIG. 1F is a view taken along line 1F-1F of FIG. 1E andillustrates the relative positions of vial 102 and cartridge 116 inhousing 304. As shown, the longitudinal axes of vial 102 and cartridge116 are parallel but offset relative to the positioning within thehousing 304. This allows for both vial 102 and cartridge 116 to beinserted into the housing 304 without interfering with the internalcomponents of the device 100, for example, the needle retractionmechanism described below.

[0071]FIGS. 2A and 2B illustrate cutaway views along lines 2A, 2B-2A, 2Bof FIG. 1F of the device 100 including vial 102 and cartridge 116. Moreparticularly, vial 102 is preferably a standard vial, for example, a 2milliliter vial, which typically comprises glass and includes apuncturable rubber stopper 112 held in place by an aluminum band orother sealing mechanism 114. The upper end of housing 304 includes agrooved portion 132 which locks the vial 102 to the housing by passingthe lip of the aluminum band 114 under a pair of spaced apart arms thathook up into the housing. A first needle 124, or other suitable means,is mounted to the housing 304 and is configured to pierce the rubberstopper 112 of vial 102 upon insertion of the vial into the lockingposition provided by aims 133. First needle 124 is fluidly connected toa first channel or tube 122 for receiving the diluent from cartridge 116as illustrated in FIG. 2B. Cartridge 116, similar to vial 102,preferably comprises a standard cartridge (for example, a 2 millilitercartridge with about 1 milliliter diluent) and includes a rubber stopper118 which is pierced by a second needle 126, or other suitable means.Second needle 126 is fixedly mounted on an extending member orcompression element 238 of housing 304 such that the cartridge ispierced upon insertion of the cartridge. First tube 122 is fluidlyconnected to the second needle 126. Upon insertion of the cartridge 116,extending member 238 or compression element of housing 304 contacts andpushes rubber stopper 118 toward the bottom of cartridge 116. In thismanner, the diluent 166 is forced up tube 122 into vial 102 to mix withthe drug 164 contained therein. In the preferred embodiment of thepresent invention, cartridge 116 contains approximately 1 milliliter ofdiluent which is forced into vial 102, resulting in a pressure insidevial 102 of approximately 2.25 bars. This pressure can be adjusted, forexample, by decreasing the amount of diluent or air in cartridge 116. Ahigher pressure inside vial 102 injects the reconstituted drug 160 morequickly.

[0072] Thus, a sterilized solution is provided wherein the diluent 166is mixed with the lyophilized drug 164 with minimal exposure to outsidecontaminants it is preferable that vial 102 containing the reconstitutedlyophilized drug 160 be visible during reconstitution and injection suchthat the user can properly visually verify that the lyophilized drug 160is thoroughly mixed with diluent 166 and that the vial 102 is verticalduring injection to ensure the compressed gas is not being injected intothe injection site.

[0073] Handle member 106 is pivotally connected to the housing 304 at afirst end by a pivoting mechanism 110 which can include a rivet or othersuitable means such that the handle member rotates in the direction ofarrow 240. Handle member 106 includes biasing mechanism 108 whichresiliently biases handle member such that the end opposite thepivotally connected end is forced away from housing 304. Biasingmechanism 108 includes an extending member from handle member 106 whichcontacts housing 304, thereby providing a resilient biasing force awayfrom the housing when the handle member is forced toward the housing.Alternatively, or additionally the biasing mechanism 108 can comprise aconventional spring, or other suitable means, interposed between housing304 and handle member 106 which provides the biasing force.

[0074] Also shown in FIG. 2A is a needle injection and retractionmechanism for injecting the reconstituted drug 160 into the person andretracting the injection needle 130 within the housing 304. Themechanism includes a first bar member 140, which is pivotally connectedat a first end by member 136, and guidably mounted at a second end tothe handle member 106 by a first coupling device 142, such as a pin,rivet, bolt, or other suitable means. Member 136 fixedly supportsinjection needle 130 and is guided by an opening 138, or needleaperture, in the housing 304. In the preferred embodiment of theinvention, injection needle 130 is in the range of a 24-28 gauge needle.The movement of first coupling device 142 is controlled by a J-shapedslot 134 which can comprise a slot or groove in handle member 106. Asecond bar member 148 is pivotally connected at a first end to firstcoupling device 142 and pivotally connected at a second end to a thirdbar member 152 by a third coupling device 150. Third bar member 152fixedly supports a third needle 128 and may be guided by internal borein housing 304. A second channel or tube 120 fluidly connects the thirdneedle 128 and injection needle 130. It is preferable to minimize thelength of tube 120 such that the residual volume of drug remaining inthe tube after injection is reduced to increase the accuracy of thedosage.

[0075] The operation of drug delivery device 100 shown in FIGS. 2A and2B is illustrated in FIGS. 3A-3D. FIG. 3A illustrates the stage at whichthe cartridge 116 is inserted forcing diluent 166 up tube 122 into vial102. It will be recalled that the rubber stopper of 118 of cartridge 116is forced to the bottom of the cartridge by member 238 as shown in FIGS.2A and 2B. This causes the diluent 166 to be forced up tube 122 whichresults in the reconstituted drug 160 being under pressure, which in thepreferred embodiment is approximately 2.25 bars. The device 100 ispreferably vigorously shaken to ensure the lyophilized drug is properlymixed with diluent 166.

[0076] In FIG. 3B, the device 100 is placed against the skin of theperson being injected. The user presses handle member 106 toward thehousing 304 in a direction shown by arrow 240A, thereby displacinginjection needle 130 from the first position within the housing to asecond position outside the housing such that the needle penetrates theskin of the body being injected.

[0077] As shown in FIG. 3C, continued pressure of the handle 106 towardsthe housing 304 causes the first bar member 140 to ride up the J-shapedslot 134. Simultaneously, second bar member 148, which includes a linearslot 244, is rotated such that first coupling device 142 ides up to thetop of slot 244.

[0078]FIG. 3D illustrates the continued pressing motion of the handlemember 106 toward the housing 304. As the handle member 106 continues topivot, the second bar member 148 forces third bar member 152 and hencethird needle 128 upward such that third needle penetrates the rubberstopper 112 of vial 102. Because the reconstituted lyophilized drug 160is under pressure, it is forced through tube 120 and thus into theperson being injected. At this point, biasing mechanism 108 iscompressed. As the handle member 106 is released, biasing mechanism 108forces the handle member away from the housing 304 as indicated by arrow240B and thus withdraws injection needle within the housing. This isillustrated in FIG. 3D. J-shaped slot 134 is beneficially provided withan end locking portion 146 which catches coupling device 142 such thatthe injection needle 130 is “locked” within the housing 304 after asingle injection. Now, the device 100 can be safely discarded.

[0079] FIGS. 4A-4K illustrate a drug delivery device 100-1 in accordancewith a preferred embodiment of the present invention wherein the samereference numbers refer to the same or similar elements. Moreparticularly, FIG. 4A illustrates the device 100-1 which includes ahousing 304-1 having a first port or opening 176 for receiving a diluentcartridge 116 aid a second port or opening 262 for receiving vial 102.In this embodiment, it is preferred that cartridge 116 containingdiluent 166 be preassembled such that the cartridge is partiallypenetrated by needle 126-1 and such that the device 100-1 (without vial102) is wrapped by a packaging material to maintain sterility prior touse. Again, it is preferable to use a standard 2 milliliter vial andcartridge that contains 1 milliliter of diluent. Thus, the user unwrapsthe packaging material and places vial 102 containing the lyophilizeddrug 164 into the opening 262. Alternatively, vial 102 and cartridge 116are packaged separately from the device 100-1 as shown in FIG. 4A. Theuser removes the sterility protector and presses the vial 102 firmlyinto the opening until needle 124-1 penetrates the rubber stopper 112.The user then forces cartridge 116 into the housing 304-1. As cartridge116 is forced into the housing 304-1, the rubber stopper 118 is firstpenetrated by needle 126-1 such that the needle extends into the diluent166. This stage is illustrated in FIG. 4B.

[0080] Continuing to insert the cartridge 116 into the housing 304-1forces the rubber stopper 118 to the bottom of the cartridge, as shownin FIG. 4C. That is to say, the first opening 176 of housing 304-1 ispreferably circular, thereby allowing the walls of cartridge 116 toenter the housing and not the rubber stopper 118. This forces thediluent 166 through needle 126-1 to a manifold or communicationpassageway 168 and into the vial 102. Again, the resulting reconstitutedlyophilized drug 160 in vial 102 is preferably under pressure of about2.25 bars. A greater or lower pressure may be necessary depending on thevolume to be injected. The device 100-1 is preferably vigorously shakento ensure the reconstituted lyophilized drug 160 is properly mixed inpreparation for injection.

[0081] It is preferable to insert vial. 102 containing the lyophilizeddrug 102 before insertion of cartridge 116 containing diluent 166 suchthat the diluent is not spilled into opening 262. In order to ensure theproper insertion sequence of vial 102 and cartridge 116, an interlockingmechanism is provided in accordance with another aspect of the presentinvention. Interlocking mechanism comprises a bar member 266 pivotallyconnected to the housing, 304-1 between the openings 176 and 262. Thebar member is configured to be moved in the direction of arrow 264 (FIG.4A) upon insertion of vial 102. Thus, as shown in FIG. 4A, bar member266 prevents cartridge 116 from being inserted. As vial 102 is inserted,it rotates bar member 266 in the direction of arrow 264 as shown in FIG.4A such that cartridge 116 can subsequently be inserted.

[0082] As shown in FIG. 4B, the device 100-1 is further provided with anactuator or pushing member 174 for displacing the injection needle 130-1between a first position within the housing 304-1 and a second positionoutside the housing. It is preferred that the injection needle 130-1extend out of the housing 304-1 in the range of 5-12 millimeters. Theinjection needle 130-1 is in the range of a 24-28 gauge needle and ispreferably a “U” type needle having a second end 172 configured topuncture sealing member 170. Sealing member 170, which can be anypuncturable material such as butyl rubber, sealingly maintains theliquid in the upper part of housing 304-1 prior to use.

[0083] It is preferable to prevent displacement of the injection needle130 when the device 100-1 is not properly oriented, for example, upsidedown, in order to prevent the compressed gas in vial 102 from beinginjected. Also, it is preferable to lock the injection needle 130-1within the housing 304-1 after a single injection to reduce exposure tothe contaminated needle. Additionally, it is preferable to only allowdisplacement of needle 130-1 after insertion of cartridge 116.Accordingly, a locking assembly 268A is provided to accomplish theforegoing.

[0084] The locking assembly 268A comprises member 268 as shown in FIG.4C having a first end configured to be moved by pushing member 174 and asecond end configured to displace a ball 270 or other appropriatemovable locking device. With the pushing member 174 in the firstposition such that injection needle 130 is within the housing, groove272 of the pushing member 174 aligns with groove 274 such that ball 270can freely travel around the groove 274 of the pushing member. When vial102 is vertically oriented with the compressed gas above the liquid,thus being properly positioned for injection as shown in FIGS. 4B and4C, ball 270 rests in the bottom of groove 274 allowing the pushingmember 174 to displace the injection needle 130. If the vial 102 is notproperly positioned (for example, the assembly being upside down suchthat compressed gas would be injected, as shown in FIGS. 4E and 4F), theball 270 is positioned within grooves 272 and 274 to preventdisplacement of the pushing member 174.

[0085] The locking assembly 268A can be further configured to allowdisplacement of the pushing member 174 only after cartridge 116 isinserted. FIGS. 4G-4L illustrate this aspect of the invention. Moreparticularly, FIG. 4G is similar to FIG. 4C except cartridge 116 isshown outside of the housing 304-1. FIG. 4H is a sectional view takenalong line 4H-4H of FIG. 4G and shows member 276 of the lockingmechanism having a slotted portion 278 therein. Member 276 is slidablewithin the housing 304-1 and configured to be moved by insertion ofcartridge 116. The lower end of member 276 is positioned within grooves272 and 274 as shown in FIG. 4L Thus, with member 276 in the positionshown in FIG. 4H, or before cartridge 116 is inserted into the housing304-1, the pushing member 174, and hence injection needle 130-1, isprevented from moving to the injection position.

[0086] When the cartridge 116 is fully inserted into housing 304-1 asshown in FIG. 4J, member 276 is moved downward as shown in FIG. 4K. Asshown in FIG. 4L, this allows slotted portion 278 to align such thatpushing member 174 and hence injection needle 130-1 can be moved to theinjection position.

[0087] With the device 100-1 properly held by the user such that vial102 is vertically oriented as shown in FIG. 4M, the user presses pushingmember 174 such that the injection needle 130-1 first extends out of thehousing 304-1, thus penetrating the skin of the person being injected.Continued pressing of pushing member 174 causes the second end 172 ofinjection needle 130-1 to puncture sealing member 170, thereby allowingthe pressurized reconstituted lyophilized drug 166 to travel from vial102 into the person being injected. It may tale in the range of 10-30seconds to deliver the injection fluid. This pressing motion compressesspring 190 such that upon release of pushing member 174, the memberreturns to the original position, i.e., the needle 130-1 is withdrawnwithin the housing 304-1 and locked therein. Insertion of the pushingmember 174 into the housing 304-1 also moves in member 268 such thatball 270 is biased against the pushing member. This is shown in FIG. 4N.When the pushing member 174 is returned to the first position, the ball270 is positioned and held within groove 272 by member 268, therebypreventing displacement of the pushing member and hence the injectionneedle 130-1 after a single injection. This configuration is illustratedin FIG. 4O. With the injection needle 130-1 locked within the housing304-1, the device 100-1 may be safely discarded.

[0088] FIGS. 5A-5C illustrate a drug delivery device 100-2 in accordancewith a preferred embodiment of the present invention. More particularly,FIG. 5A illustrates the device 100-2 with the cartridge 116 installedbut not inserted or penetrated by any needle, and the vial 102 in placeready to be inserted. FIG. 5B illustrates the inserted vial 102, whileFIG. 5C shows the subsequently inserted cartridge 116. At this stage,the diluent from cartridge 116 has been transferred to vial 102,resulting in a pressurized liquid in the vial. The device 100-2 isvigorously shaken to ensure proper mixing of the reconstitutedlyophilized drug. The device 100-2 is now ready for injection. It shouldbe noted that the housing 304-2 advantageously includes a cutawayportion 254 which allows the user to visually inspect vial 102 to verifythat the lyophilized drug 160 is thoroughly mixed with diluent 166 andto verify that vial 102 is vertically oriented during injection toensure air is not being injected into the injection site.

[0089] FIGS. 6A-6C are plan views of a similar device 100-3corresponding to FIGS. 5A-5C, respectively. Accordingly, FIG. 6Aillustrates the cartridge 116 installed but not punctured by needle126-3. Vial 102, containing the lyophilized drug 164, is also shownready to be inserted into housing 304-3.

[0090]FIG. 6B shows the inserted vial 102 which is punctured by needle124-3. Vial 102 pushes first against surface 178-3 of puncturing device182-3 and pushes device 182-3 downward before being pierced by needle124. Pushing puncturing device 182 downward sets a spring which (as willbe explained in FIGS. 7A-7C) moves puncturing device upward such thatneedle 128-3 penetrates vial 102. Alternatively, the spring can bepreloaded. As shown, needles 124-3 and 126-3 are fluidly connected by amanifold 127 comprising a channel 129 or tube. Upon insertion ofcartridge 116, the rubber stopper is first pierced by needle 126, and ascartridge 116 is further inserted into the circular opening 176-3 ofhousing 304-3, the rubber stopper 118 is forced to the bottom ofcartridge 118, thereby forcing the diluent 166 through the manifold 127into vial 102. This also compresses the gas that was heretoforecontained in the vial 102 to a pressure sufficient for injection. Theresulting stage is shown in FIG. 6C. The device 100-3 is preferablyvigorously shaken to ensure proper mixing of the lyophilized drug 164.Now, the device 100-3 is ready to inject the reconstituted drug solution160 contained in the vial 102.

[0091] FIGS. 7A-7C illustrate partial perspective views of the device100-2, 100-3 shown in FIGS. 5A-5C and 6A-6P. More particularly, FIG. 7Ashows the pushing member 174-3 including an internal bore with member252 slidably contained therein. Member 252 fixedly supports injectionneedle 130 which is in fluid communication with needle 128 via tube orchannel 120. Needle 128 shown in FIG. 7A has yet to pierce the rubberstopper 112 of vial 102. Needle 128 is fixedly supported by puncturingdevice 182. As the pushing member 174-3 is pressed toward the housing304-3 (i.e., in the direction of arrow 180), a first spring 190 iscompressed allowing the member 252 to move downward until contacting thehousing. This allows injection needle 130-3 to extend out of needleaperture 256 in housing 304-3 to penetrate the skin of the person beinginjected. The spring 190 is set such that it creates both axial androtational movement. Only upon complete insertion of the vial 102 is therotational movement of the spring enabled which in turn enables thepuncturing of the vial 102. In the preferred embodiment, injectionneedle 130-3 extends in the range of 5-12 millimeters out of the housingthrough needle aperture 256. The injection needle 130 partiallyextending out of the housing 304-3 is illustrated in FIG. 7B.

[0092] As the pushing member 174 is further pressed toward housing304-3, spring 200, which is stiffer than spring 190, is compressedallowing ridge 258 of pushing member 174-3 to contact puncture device182. This causes rotation of puncturing device 182 in the direction ofarrow 186 as shown in FIG. 7C, such that surface 178 no longer contactsthe vial 102. The spring 190 which, as described above, was loaded uponinsertion of vial 102, now causes the puncturing device 182 to rotate inthe direction of arrow 184, thereby causing needle 128 to penetrate therubber stopper 112 of vial 102. This arrangement is illustrated in FIG.7C. The reconstituted drug 160 is forced by the compressed gas withinvial 102 through injection needle 130 into the person being injected ina time range of approximately 10-30 seconds.

[0093] FIGS. 8A-8E illustrate a drug delivery system 100-4 in accordancewith a preferred embodiment of the present invention wherein the samereference numbers refer to the same or similar elements. Moreparticularly, FIG. 8A illustrates the device 100-4 which includeshousing 304-4 having a first port or opening 176-4 for receivingcartridge 116 and a second port or opening 262-4 for receiving vial 102.

[0094] Vial 102 containing the reconstituted drug 164 is inserted intothe housing 304, followed by the insertion of cartridge 116 containingthe diluent 166. Again, a rubber stopper of the cartridge 116 is forcedto the bottom of the cartridge which forces the diluent under pressureinto vial 102. This stage is shown in FIG. 8B. Advantageously, thehousing 304-4 includes a cutaway portion 400 such that vial 102 issubstantially visible during reconstitution and injection. This allowsthe user to visually verify that the drug is properly reconstituted andthat the vial 102 is vertically oriented during injection with thecompressed gas above the reconstituted drug.

[0095]FIG. 8C is a rear view taken of FIG. 8B and illustrates theinjection of the reconstituted drug. More particularly, the pushingmember or actuator 174-4 is pressed into housing 304-4 which forcesinjection needle 130-4 out of the housing and into the person beinginjected. In the preferred embodiment, the injection needle extends outof the housing in the range of 5-12 millimeters. The reconstituted drug,in fluid communication with the vial 102, is transferred from the vialand into the person being injected. FIGS. 8D-8F are isometric views ofthe device 100-4 in the stages shown in FIGS. 8A-8C, respectively.

[0096]FIGS. 10A and 10B graphically illustrate system characteristics ofa preferred embodiment of the drug delivery device. To provide effectivedelivery of a specified amount of fluid and minimize patient discomfort,the system requires a sufficient fluid pressure in the delivery vialthat is manually actuated by the user within a short time period. FIG.10A shows the pressure (millibars) and weight (grams) characteristics ofthe system during a delivery period of about 30 seconds for a deliveryvolume of about 1.6 milliliters. FIG. 10B illustrates test results ofthe delivery of 1.6 milliliters into different animals using a singledrug delivery device for the same time period.

[0097] Referring to FIGS. 11A-11D, cutaway views of a preferredembodiment of a diluent container subassembly and a manifold, which maybe used with the drug delivery devices or with an ordinary syringe orother drug delivery devices, are illustrated. The diluent containersubassembly 300 includes a preassembled compression portion 310 whichallows the user to hold the diluent container 312, which can be in theform of a compressible sealed bag, and insert it into a needle 314. Thediluent container 312 contains about 1 milliliter diluent and acontrolled volume of gas, such as air, for example, and upon insertioninto housing 304-6, is pierced by the needle 314. During storage orshelf life, the diluent container 312 is sized to allow for expansion ofthe container as a result of changes to the environment. In addition,the compression portion 310 is used to compress the exterior of thediluent container and apply pressure to the contents of container duringdelivery of the diluent for mixing. The diluent containers are formedfrom flexible, collapsible materials, for example, polyethylene,polypropylene and nylon. The compression portion 310 includes a sliderelement 316 and two longitudinally extending arms 318, 320 extendingtherefrom. Two cylindrical drums 322, 324 are spaced between thelongitudinally extending arms 318, 320.

[0098]FIG. 11A illustrates the diluent container subassembly 300positioned in the housing 304-6 of the drug delivery system inaccordance with the present invention. FIG. 11D further illustrates thefully compressed state of a preferred embodiment of the diluentcontainer subassembly 300. The slider element 316 of the compressionportion 310 translates in at least one axis, for example, in theillustrated embodiment, it can move up or down. The downward movement ofthe slider element 316 causes the diluent container 312 to wrap aroundthe cylindrical drum 324 which compresses the contents of the diluentcontainer 312, thus forcing the diluent from the container 312 andthrough the needle 314 and into the vial 102. The movement of the sliderelement 316 is limited by an end of travel position. At this end oftravel position, the slider element 316 may be locked by a lockingmechanism which ensures that the diluent container is kept compressed.

[0099] A manifold 330 includes two needles 314, 332 fixedly mounted atthe ends of an extending member 334. The needles can also comprise apenetrating member that is formed from an injection molded material suchas medical grade polycarbonate or acrylic with the required level ofrigidity to penetrate the vial or container. A channel 331 provides forfluid communication between the needles 314 and 332. Needle 314 piercesthe diluent container 312 upon insertion of the container, while needle332 pierces the vial 102 upon insertion of the vial containing thelyophilized drug 164. In a preferred embodiment of the presentinvention, container 312 contains approximately 1 milliliter of diluentand a controlled volume of air which is forced into vial 102, resultingin a pressure inside vial 102 of approximately 2.25 bars. The pressureinside vial 102 results from forcing the controlled volume of air in thediluent container 312 into the rigid volume in the vial 102. Thus, thediluent 166 is forced into vial 102 to mix with the lyophilized drug 164contained therein. The entire assembly is preferably shaken to ensurethe reconstituted drug 160 is properly mixed in preparation forinjection. The vial 102 is vertically oriented during injection toensure air is not being injected into the injection site.

[0100] Referring to FIG. 11C, the injector needle 130-6 is shown in afirst position within the housing 304-6. As described hereinbefore, theinjection needle 130-6 is in the range of a 24-28 gauge needle and ispreferably a “U” shaped needle having a second end 172-6 configured topuncture sealing member 170-6. An area 171 is located adjacent to thesealing member 170-6 and is in communication with the channel 331 asshown in 11B.

[0101] When the user compresses the button 305, it causes the needle130-6 to penetrate the skin and the second end 172 to penetrate thesealing member 170. The drug and diluent solution will flow from theneedle 332, through the channel 331, and area 171 and to the user viathe injector needle 130-6. As the user compresses the button 305, whichis spring loaded by spring 306, a pair of rating pawls 307, 308 fittogether and prevent the button from being pulled out and the reuse ofthe device as shown in FIG. 11C.

[0102] FIGS. 12A-12B illustrate perspective views of a preferredembodiment of the diluent container subassembly 300 and provide furtherdetails of the components of the compression portion 310. Thecylindrical drum 324 is slotted such that the diluent container can beinserted therein. The cylindrical drum 322 serves as a backing drum.Thus, the diluent container 312 is typically inserted between thecylindrical drum 324 and the backing drum 322. The drum apparatus 322,324 moves in a rack and pinion gear apparatus 340. An end of travelposition 342 in the rack and pinion gear apparatus 340 constrains themovement of the cylindrical drum 324 at its end of movement position.This end of travel position correlates with the end of the wrapping ofthe diluent container 312 around the cylindrical drum and maximumcompression of the contents of the container. A flange 344 can be usedto hold the diluent container 312 at the bottom of the subassembly 300.The diluent container 312 can be sealed by means of heat weldingtechniques or ultra sonic techniques to the flange 344 after it has beenfilled with the diluent. The longitudinally extending arms 318, 320 inthe compression portion 310 each comprise two members 350, 352, as shownin FIG. 12B. A cylindrical drum is attached to each member. The twomembers 350, 352 are spaced apart from each other to accommodate thewrapping of the diluent container on the cylindrical drum 324.

[0103] Referring to FIGS. 13A-13B, cutaway views illustrate an alternateembodiment of the invention similar to that shown in FIGS. 11A-11Dincluding a manifold 350. The manifold 350 has two needles 352, 354 forthe purpose of piercing the vial 102 and diluent container 312respectively. Once the diluent 166 and the controlled volume of air areforced to move into vial 102, the diluent mixes with the lyophilizeddrug 164 and results in the reconstituted drug 160 which is underpressure. Because the reconstituted drug is under pressure due to thecontrolled volume of air, it is forced through the needle 352 and intothe person being injected through a needle 351 that is actuated bymovement of pushing member 353. This embodiment of the device provides auser comfort as it does not have to be vigorously shaken to ensure thereconstituted lyophilized drug 160 is properly mixed in preparation forinjection. The controlled volume of air facilitates the mixing of thediluent and the lyophilized drug. The pushing member 353 displaces theinjection needle 351 between a first position within the housing 304 anda second position outside the housing, or in an injection state.

[0104] It is preferable to prevent displacement of the injection needle.351 when the device 100-7 is not properly oriented, for example, upsidedown, in order to prevent the compressed gas in vial 102 from beinginjected. Also, it is preferable to lock the injection needle 351 withinthe housing 304-7 after a single injection to reduce and preferably toprevent the exposure to the contaminated needle. Additionally, it ispreferable to only allow displacement of needle 351 after insertion ofdiluent container 312. Accordingly, a locking mechanism comprisingmember 268 as shown in FIG. 4B is provided to accomplish the foregoing.The member 268 has a first end configured to be moved by pushing member353 and a second end configured to displace a movable locking device,substantially similar to the device shown in FIG. 4B.

[0105] With the device 100-7 properly held by the user such that vial102 is vertically oriented, the user presses pushing member 353 suchthat the injection needle 351 first extends out of the housing 304-7,thus penetrating the skin of the person being injected. Continuedpressing of the pushing member 353 causes the second end 355 ofinjection needle 351 to puncture sealing member 357, thereby allowingthe pressurized reconstituted drug 166 to travel from vial 102 into theperson being injected. It may take in the range of 10-30 seconds todeliver the injection fluid. The pressing motion compresses spring 359such that upon release of pushing member 353, the member returns to theoriginal position, i.e., the needle is withdrawn within the housing 304and locked therein.

[0106] Referring to FIG. 14, a cutaway view illustrates a manifold ofanother preferred embodiment of the drug delivery device 100-8 inaccordance with the present invention. The manifold 350 has two needles352, 354 for the purpose of piercing vial 102 and diluent container 312,respectively. A flange, substantially similar to the flange 127 shown inFIG. 6B, holds the septum or stopper 313 in place in the container 312.An extending member or communication chamber 356 which is in fluidcommunication with the needles 352, 354, has a membrane such as ahydrophilic membrane or barrier 360 disposed therein. It should be notedthat the hydrophilic membrane needs to be wetted before it functions tominimize or preferably prevent the flow of gas into a user's tissue. Thehydrophilic membrane allows gas, for example, air to pass freely till itcomes in contact with liquid and gets wet. Thus, when wet, no air suchas the controlled volume of air in the diluent container 312 can passthrough the hydrophilic membrane, preventing air from entering theuser's tissue. The presence of the hydrophilic membrane prevents riskscaused by any wrong use of the device 100-8 by the user such asincorrect positioning of vials or containers.

[0107] Referring to FIGS. 15A-15B, cutaway views illustrate anotherpreferred embodiment of a manifold of the drug delivery device inaccordance with the present invention. The needle 352 pierces the vial102 while needle 354 pierces the diluent container 312. The needle 354and channel 352 on spike 352A are in fluid communication. Diluent 166moves from the diluent container 312 into vial 102, thus mixing with thelyophilized drug to result in a reconstituted drug. A channel 358 is incommunication with an area 361 sealed by a stopper 313. Channel 358 alsoincludes a hydrophilic membrane. Thus, upon the introduction of air tothe channel, the membrane expands in the presence of air and disallowsthe passage of air therethrough.

[0108] In use, the user presses the button 363 which first movesinjector needle 130 into the users skin. Further movement of the button363 causes piercing member 172 to penetrate the stopper 313. Thisenables liquid drag/diluent solution to move, via the air pressure inthe vial 102 through the injector needle 130 and the user's slain.

[0109] It should be noted that the embodiment illustrated with respectto FIGS. 15A and 15B being more position independent, is not subject toair blocking the flow of liquids through the gas impermeable membraneuntil all the drug solution has been transferred out of the vial 102.FIG. 15A shows the position of channel 358 relative to channel 352.Thus, only if the vial 102 is completely filled with air would it passinto charnel 358. In contrast, the embodiment illustrated with respectto FIG. 14 and the absence of the lower channel 358 is more positiondependent and thus subject to air blocking the flow of liquids throughthe gas impermeable membrane even while the drug solution is beingtransferred out of the vial 102.

[0110] Further, it should be noted that the delivery times of the drugsis dependent on the volume of vial which maybe adjusted. The pressure isadjusted in part by adjusting the vial volume size. A large vial volumeof air relative to the drug would result in greater air pressure andfaster drug delivery.

[0111] In the preferred embodiments of the present invention the drugvials and the diluent containers are shown as being inserted in thehousing 304 and aligned in the same direction along parallel axes. Inthe alternative, it is contemplated that the vials and containers maynot be aligned in the same direction along parallel axes. The vials andcontainers may be inserted along two different axes that are oriented atoblique or orthogonal angles relative to each other.

[0112] Referring to FIG. 16 a cutaway view illustrates an alternatepreferred embodiment of an injection device 236 in accordance with thepresent invention. The device 236 facilitates the sterilized injectionof a prefilled cartridge or vial containing an injectable liquid, forexample, a vial containing a liquid drug 160. The device 236 includesfirst opening 161 for receiving vial 102 and a manifold 370 includingmember 372 sealingly engaged with the first opening 161. Member 372fixedly supports needle 374 and is supported by a collapsible volume,such as bellows 378, or any other device capable of injecting a fluidsuch as a gas upon being compressed. A check valve 380 ensures that theflow from the bellows is unidirectional, that is, the drug underpressure can not enter the bellows 378. The check valve 380 comprises atubular member 381 adapted to deliver gas, for example air, to the vial102. Air is moved out of the bellows and into the tubular member 332 bycompressing, the bellows 378. The check valve 380 allows the flow of airout of the bellows 378 and into the vial but disallows the reverse flowof air from the vial into the bellows. Air from the bellows 378 isforced up through needle 374 and into vial 102 applying pressure to thecontents of the vial 102. The liquid drug 160 is under pressure and isinjected into the user directly from the vial 102. The injection processis the same as discussed earlier with respect to embodiments in FIGS.13-15, in that the use of a J-shaped needle assembly is compressed intothe skin to activate injection. As discussed earlier, due to the natureof the hydrophilic material, a hydrophilic membrane 360 in the drugdelivery path minimizes and preferably prevents gas from being injectedinto the user.

[0113] Referring to FIGS. 17A-17C, cutaway views illustrate an alternateembodiment of the drug delivery device 100 in accordance with thepresent invention. The diluent container comprises a syringe 390. Whenpressure is applied to a plunger shaft 392, the diluent 166 is forcedout of the syringe 390 through the channel 398 and into the contents ofvial 102 via the needles 394, 396 which are in fluid communication witheach other through the member 398. Thus, the diluent 166 is provided tovial 102 under pressure and is mixed with the reconstituted drug toresult in a reconstituted drug solution ready for injection or deliveryunder pressure to a patient. The drug solution is delivered to a userusing a u-shaped needle assembly as disclosed with respect to FIGS.13A-13B, 14, and 15A and 15B. This syringe embodiment facilitates theuse of a standard prefilled container or cartridge containing only adiluent. The device is flexible and does not require special means ortraining.

[0114] The present invention includes alternate preferred embodiments ofinjection devices. FIGS. 9A-9F illustrate an injection device 236 whichfacilitates the sterilized injection of a prefilled cartridge or vialcontaining an injectable liquid, for example, a vial containing areconstituted drug 160. It is preferable to use a standard vial, forexample, a 2 milliliter vial, with this device 236. As shown in FIG. 9A,device 236 includes a first opening for receiving the vial 102 and amanifold including member 232 which is slidably and sealingly engagedwith the first opening. Member 232 fixedly supports needle 224 and issupported by a collapsible volume, such as bellows 228, or any otherdevice capable of injecting air upon being compressed. Needle 224 is insealed communication with the bellows 228 as shown in FIG. 9A. The vial102 is pressed into the housing 304-5 such that needle 224 pierces therubber stopper 112. This arrangement is shower in FIG. 9B.

[0115] The vial 102 is further pressed into the housing 304-5 whichforces member 232 to compress bellows 228, thus forcing the aircontained in bellows 228 up through needle 924 and into cartridge 116.Now, as illustrated in FIG. 9C, the cartridge 116 is under pressure forforcing the drug 166 into the person being injected. The bellows orother compression device can also be actuated by member 174-5.

[0116] As shown in FIGS. 9A-9F, device 236 is further provided with apushing member 226 for displacing the injection needle 130-5 between afirst position within the housing 304-5 and a second position outsidethe housing, or in an injection state. In the preferred embodiment adistal end of the injection needle 130-5 can extend out of the housing304-5 in the range of 5-12 millimeters. In this particular embodiment,the injection needle 130 is preferably a “U” type needle having a secondend 250 configured to puncture sealing member 230. Sealing member 230,which may comprise any puncturable material such as butyl rubber,maintains the liquid in the upper part of housing 304. As the userpresses pushing member 226 into housing 304, the first end of theinjection needle 130 first penetrates the skin of the person beinginjected as shown in FIG. 9D. Continued pressing of pushing member 226into the housing 304 causes the second end 250 of injection needle 130-5to puncture sealing member 230, thereby allowing the reconstituted drug160 to travel from cartridge 116 into the person being injected. This isillustrated in FIG. 9E. The pressing of the pushing member 226 into thehousing 304-5 compresses a spring such that upon release of pushingmember 226, the member returns to the original position, i.e., theinjection needle 130-5 is in the first position within the housing 304-5as shown in FIG. 9F. This embodiment may be further provided with alocking mechanism similar to that disclosed in FIGS. 4A-4K. With theinjection needle locked within the housing 304-5, the device 236 may besafely discarded.

[0117] Further, FIGS. 18A-18C illustrate an injection device inaccordance with an alternate preferred embodiment of the presentinvention. More particularly, the drug delivery device 400 includes astraight needle 402 having a lancet 404 disposed on a first end. Acavity 405 in the septum 406 contains a liquid drug under pressure. Thestraight needle 402 includes a side hole 407 disposed on the shaft. Thesecond end 408 of the straight needle is blocked. In operation, as shownin FIGS. 18A, 18A-1, 18B and 18-1, when the member 410 is moved forwardtoward the housing 412, the injection needle 402 is displaced from afirst position in the housing 412 to a second position outside thehousing such that the needle 402 penetrates the skin of the user. Afterthe lancet 404 penetrates the user's tissue, continued pressing motionof the member 410 toward the housing causes the side hole 407 to be influid communication with the cavity 405 of the septum 406 creating apath for the drug under pressure to flow into the user's tissue. Thestraight needle punctures the septum 406 at two locations. As shown inFIG. 18C, as the member 410 is released, the injection needle iswithdrawn within the housing 412.

[0118] More particularly, referring to FIG. 18A-1, a 3 part ringstructure including member 414, latch 416, gap 418 and spring 419, asshown in FIG. 18A provide an interlocking system. This safety mechanismwhich includes the members 410, 414, latch 416, gap 418 and spring 419provides an interlock to ensure against reuse of the drug deliverydevice 300 and exposure of needle 402 after the first use. Once themember 410 is compressed the mating ridges 413A and 413B come together.The ridges are angled on one side to allow ridge 413B to pass under 413Awhen member 410 is depressed against the housing 412. The ridges arepressed together when the force of the spring 419 moves member 410 awayfrom the housing 412. Because the ridges interface at a right angle tothe direction of movement of the member 410 they serve to preventfurther movement by the member and the needle 402. This mechanismensures that the device 400 is not reused.

[0119] FIGS. 19A-19F illustrate cutaway views of alternate preferredembodiments of systems which allow reconstitution of drug and subsequenttransfer into a drug delivery device in accordance with the presentinvention. Once the drug is made into a solution it may be transferredinto a user by means of direct injection as shown in FIG. 11, forexample, or into a drug delivery device such as an infusion pump,needleless injector or the like. The systems include a vial 420containing a predetermined volume of a drug and a vial 422 containing avolume of a diluent. The use of standard vials facilitate the use of thedrug delivery device by different drug suppliers.

[0120] An air source 424 maybe included for the delivery of drugs. Withdrugs of higher viscosity, the use of pressure becomes more important.As illustrated in FIG. 19A, the sources of pressurized air can vary andmay include, but are not limited to, a compressed air delivery supply426, a chemical gas generator 428, a standard syringe 430 and acollapsible volume container, such as a bellow container 432. The airsource supplies the driving force to the diluent volume which moves thediluent solution 434 into the standard lyophilized drug vial 420. Oncereconstituted, the liquid drug is transferred via the air separator,such as a hydrophilic membrane 436, to a drug delivery system. It shouldbe noted that spike 438 in the diluent vial 422 and spike 440 in thedrug vial 420 each have two paths. The spike 438 has a first path forcompressed air to enter the diluent vial 422 and a second path for thepressurized diluent 434 to be in fluid communication with the drug vial420. The spike 440 has a first path for the pressurized diluent to enterthe drug vial 420 and a second path for the delivery of the drugsolution into a drug delivery device. As discussed earlier, it iscontemplated that other drug delivery devices may be received into thissystem to receive the drug solution.

[0121] Referring to FIG. 19B, the air source is a compressed aircanister 426. The compressed air canister typically is a standardaddition for domestic drag delivery devices. The user attaches thecompressed air canister 426 to the drug delivery system 450 andpunctures a seal 452 located in the compressed air canister. The aircanister is then in fluid communication with the diluent vial 422 bymeans of channel 453. Air is released from the compressed air canister426 and is introduced into the diluent vial 422, which in turn forcesthe diluent solution 434 to move into the drug vial 420 via channel 455.After reconstitution is completed, the liquid drug is ready to betransferred. The concentration of the reconstituted drug can becontrolled in this and other embodiments by changing the quantity ofdiluent transferred to reconstitute the drug. A hydrophilic membrane 436in the drug delivery path minimizes and preferably prevents gas frombeing transferred to the drag delivery device.

[0122]FIG. 19C shows a chemical gas generator 428 as the air source usedin this particular embodiment to deliver the diluent 434 under pressureto the lyophilized drug vial. The chemical gas generator 428 includes achemical compartment 456 which typically contains two materials 458,460. The two materials 458, 460 can be two liquids or a liquid and asolid palette 460 that are separated during shelf life. It should benoted that the materials used in the chemical compartment 456 and thereaction that ensues during the mixing of the materials are safe andbiocompatible. Pushing a member 462, in the chemical compartment 456results in tearing of a seal 464, for example, aluminum foil, whichseparates the two materials 458, 460 during shelf life. The twomaterials are then in fluid communication and react to produce a gassuch as, for example, carbon dioxide. The chemical gas generator 428also includes a gas compartment 466 which is typically an air reservoirhaving a flexible enclosure 468. The carbon dioxide produced in thechemical compartment 456 due to the reactions enters the gas compartment466 and is accommodated in the flexible layers 468 that form the gascompartment. The movement of the flexible layers 470, 472 force the airor carbon dioxide into the diluent vial 422 through the air pathway 423.It should be noted that the gas compartment 466 has a double layer 470,472 comprising the flexible containment area. The two layers 470, 472provide for safety as if the air or gas generated as a result of thereaction in the chemical compartment does leak, it can be accommodatedbetween the flexible enclosure 468 of the gas compartment 466. Further,the gas compartment 466 is vented using a gas leakage pathway or ventport 474. The air that is released from the chemical gas generator 428enters the diluent vial 422 via the channel 423 which in turn forces thediluent solution 434 to move into the drug vial 420 via the channel 425.After reconstitution is completed, the drug is ready to be used, and istransferred to a drug delivery system such as one described with respectto FIG. 9B.

[0123] Referring to FIG. 19D, the air source used in this particularembodiment to deliver the diluent under pressure is a standard syringe430 or an air reservoir. The syringe 430 is locked at an end of travelposition. When press-are is applied to a plunger shaft 480 the air isforced out of the syringe 430 and into the contents of the diluent vial422 through the needle 482 and needle 434 which are in fluidcommunication through the member 484. The diluent 434 is then forcedinto the drug compartment or drug vial 420 via member 484 under pressurewhich provides for the mixing with the lyophilized drug to result in areconstituted drug which is then ready for injection or delivery underpressure to a user. In an alternate embodiment, a lever can be includedto reduce the force required for pushing the plunger member 480. Thelever will increase the displacement and thus delivery of pressurizedair to the diluent container in this case, the drug solution may beinjected as shown in FIG. 19D, the sectional of which is the same asshown and described in other needle assemblies, for example, shown inFIGS. 11, 13, 14, 15, 16, and 32 or transferred into a drug deliverydevice.

[0124] Referring to FIG. 19E, the air source used in this particularembodiment to deliver the diluent under pressure to the lyophilized drugis a collapsible volume container such as a bellow container 432. Acheck valve 488 or a one-way valve insures that the flow from the bellowcontainer 432 is unidirectional, that is, the drug or diluent can notenter the bellows. The check valve 488 comprises a tubular member 490adapted to deliver gas, for example air, to the diluent vial 422. Theresilient nature of the bellows is checked by the check valve 480 whichdoes not allow air to enter the bellows and thus reinflate the bellowsonce the bellows have been compressed and air has exited. Oncecompressed, air contained in the bellows 432 is forced through needle438 and into the diluent vial 422 via channel 491 applying pressure tothe contents of the diluent vial. The diluent solution 434 in turn, isdelivered under pressure to the drug vial 420 where the drug isreconstituted and can be transferred either by injection as describedabove or into a drug delivery device, as also described and shownrelating to the embodiment of FIG. 19A.

[0125] Referring to FIG. 19F, the air source used in this particularembodiment to deliver the diluent under pressure is cylinder 490. Thisembodiment is similar to the embodiment containing a standard syringe asdescribed with respect to FIG. 19D. The plunger 492 is depressed tocompress the air in the cylinder 490. The air is driven into the diluentvial 422 through channel 494 which brings the cylinder and the diluentvial in fluid communication. The pressurized diluent in diluent vial 422then moves into the vial 420 and mixed with the drug. The pressurizeddrug solution is then ready to be delivered. This can either comprisedelivery to a drug delivery device as described with respect to theembodiment of FIG. 19A or injected as shown in the present embodimenthaving a straight needle assembly as shown and described in FIG. 18.

[0126] Referring to FIGS. 20A-20C, an alternate embodiment of the drugdelivery system 498 in accordance with the present invention includesstandard vial 500 containing a liquid drug 502. A volume of gas, forexample air, contained in an air chamber 504 is introduced in thestandard liquid drug vial 500, creating air pressure above the liquiddrug which allows for delivery of a liquid drug under pressure. Theusage is position dependent, that is the delivery of the liquid drug, isperformed with the standard vial 500 in a vertical position. Inaddition, a hydrophilic membrane minimizes or preferably prevents theintroduction of the extra volume of air into the user's tissue.

[0127] In use, as shown in FIG. 20A, the standard vial 500 containingthe liquid medicament 502 is inserted into the drug delivery device 498in accordance with the present invention. An air chamber 504 is providedwhich upon insertion of the drug vial 500 and the puncturing of the seal506 of the vial, is in fluid communication with the drug vial. Onceinserted, the lip 505A of a standard vial 500 is locked into position bymeans of a pair of arms 505 having ridges 507 projecting inwardlytherefrom. The injector system is the straight needle 402 embodiment asdisclosed in FIGS. 18A-18C; Once the air from the air chamber isintroduced into the standard drug vial 500 the liquid drug ispressurized and is ready to be injected using the injector systemdescribed with respect to FIGS. 18A-18C. After injection into the user'stissue, the needle is retracted automatically. The drug delivery device498 is then disposed.

[0128] Referring to FIG. 21, an alternate preferred embodiment of a drugdelivery system 510 which uses standard vial 500 containing a medicamentis disclosed. A plunger 512 is included in the drug delivery device 510.In order to reduce forces which are required to insert the standard vial500 in the drug delivery device 510. In an alternate embodiment, thedrug delivery system 510 can have a compact configuration without aplunger. Snaps 514 lock: the standard vial 500 into position. Snaps 516hold the end portion of the vial having the seal 506 in place to ensurethat the spike 518 pierces the seal 506 of the vial 500 before the vialis moved in the downward direction. Air in the air chamber 520 isdelivered to the vial 500 when the air is compressed and displaced bythe downward movement of the vial 500. The liquid drug under pressure isdelivered to an injector using tubing 522. A hydrophilic membrane 524minimizes or preferably prevents gas from entering the user's tissue.The injector systems used can be similar to one described with respectto FIGS. 18A-18C. The member 410 is moved to displace the injectionneedle 402.

[0129] Referring to FIGS. 22A-22E, the views illustrate an alternatepreferred embodiment of the drug delivery system 530 in accordance withthe present invention. This particular embodiment may be used as areconstituted system and a drug delivery system and includes two vials532, 534 a first containing a diluent 533 and a second containing thelyophilized drug 535. In addition, there is an air delivery system forpressurizing system, such as a built-in air cylinder 533 in fluidcommunication with the diluent vial 532 which is disposed between thelyophilized drug vial 534 and the diluent vial 532. Air is pushed intothe diluent vial 532 forcing the diluent 533 from its vial into thelyophilized drug compartment or vial 534. After reconstitution iscompleted, the liquid drug is ready for injection. A hydrophilicmembrane is used as an air separator to minimize or preferably preventthe entry of air into the user's tissue. This particular embodiment usesa straight needle 402 injector system as described with respect to FIGS.18A-18C. Additionally, a positioning interlock, such as the mechanism,described with respect to FIGS. 2A-2B is used. Further, in an alternateembodiment, the air cylinder can be replaced with a standard syringe tobe the air source as shown in FIGS. 22D and 22E. A check valve (as shownin FIG. 16) disposed in the air inlet between the syringe and manifoldis included in the embodiment containing the syringe. The drug deliverysystem of the present invention is used to deliver an accurate volume ofa drug solution. The predetermined volume can be delivered usingdifferent methodologies. A first embodiment controls the dose bychanging the height of the outlet spike 535 in the liquid drug vial 537as shown in FIG. 23A, i.e. the higher the spike, the lesser is theamount of drug transferred out of the vial 537. The spike is adjusted bymeans of threads 539 upon which the spike rotates or upon which itsealably slides. This can be used for to transfer or to inject the drugsolution. Another preferred embodiment which increases the accuracy ofthe volume of drug delivered uses the residual drug volume as aparameter to indicate the volume delivered. One way of controllingdelivered drug solution volume is to use the assembly shown in FIG. 23B.After the drug is pushed in solution in vial 102 the solution may bepulled into cavity 541 by piston 555. The cavity 541 has indicationsthereon to aid the user in determining the proper volume. At the desiredlevel, the piston is stopped. The drug solution is then transferred fromthe cavity 541 either via a needle into a user or into a drug deliverydevice. Yet another embodiment to provide an accurate volume of drug isdisclosed with respect to FIGS. 24A-24C and FIG. 25. The reconstitutionsystem having the vial containing the reconstituted drug is essentiallyused as a filling station by a detachable delivery device, for example,a standard syringe or a pen type pump.

[0130] Referring to FIGS. 24A-24C a position independent injector system540 is illustrated. The drug 545 is reconstituted similar to thedescription provided with respect to earlier systems such as illustratedin FIG. 19F. After the drug has been reconstituted it can be aspiratedby a conventional standard syringe 542 for the exact dose required. Theaccuracy using this method is about +/−5%. The fluid level in the cavity550 is controlled by adjusting the pressure and geometry of the device540. The needle is held in place by the elastomeric septum or stopper552. In use, once the reconstituted drug is aspirated into the syringe542 by moving plunger 548 which moves the stopper 554 upwards allowingthe syringe 542 to be filled with the liquid drug, the syringe 542 isremoved from the drug delivery device 540. The accuracy of the volume ofthe liquid drug delivered is determined by the scale on the syringe. Theuser then injects the drug and disposes of the syringe by one of severalpotential ways. One of the ways of disposing the syringe is by attachingthe syringe to the open cavity 550 left in the drug delivery device 540.A second way is by securing the needle 547 prior to disposing thesyringe by locking it with a piece of plastic tubing. The system 540 andprocedure used is free of air inclusions and does not require an airseparator. The syringe needle 547 is placed in a closed cavitypenetrating a septum 544 and thus allows for fluid communication betweenthe needle 547 and the reconstituted drug. The volume of the closedcavity is designed to ensure the availability of the liquid drug to theneedle 547 under controlled pressurized conditions. The position of thesyringe piston 548 is fixed under pressurized conditions and the dose ismanually aspirated from the syringe.

[0131] Referring to FIG. 25 an alternate preferred embodiment of thedrug delivery system 540 as described in FIGS. 24A-24C is illustrated.The reconstitution stage is similar to the one described with respect toFIGS. 24A-24C. However, the injector system including an attachabledelivery device is different. The user dials or tunes the required doseusing a pen type pump 560 that includes a dial 562 that is inserted intothe drug delivery device. The dialing process retracts a floating pistonwhich moves upward and creates an internal pressure which provides foraspiration of the reconstituted drug. A trigger 564 releases a preloadedspring to push the floating piston. Thus aspiration occurs by dialingthe dose into the pen-type injector. Once the pump 560 is filled asindicated by an indicator 566, it is disconnected from the fillingdevice. Injection and disposal of the pump is performed afterdisconnection with a process similar to the process described withrespect to FIGS. 2A-24C.

[0132] FIGS. 26A-26D are perspective views of a drug transfer systemhaving a drug delivery device 510 in accordance with the presentinvention; A diluent vial is inserted in a cavity 572 and a lyophilizeddrug vial is inserted in cavity 574. A cavity 576 accommodates an airpressurization system to deliver drugs having a low level of viscosity.Further, the drug transfer system includes all access 578 to receive adrug delivery device. The drug is transferred thereto via a needle 580.

[0133] FIGS. 27A-27C are cutaway views of a preferred embodiment of atransfer system 600 in accordance with the present invention. Oncepressurized by the air in cavity 603, the liquid drug from vial 602 istransferred to a drug delivery device 604 via an extension 606. Theliquid drug flows out of the vial 602 through spike 608 and through thetubing 6110 into the needle 616 which is received into the drug deliverydevice 604.

[0134] Referring to FIG. 27B, the drug delivery device 604 is attachedto the transfer system 600. The filling process continues until theentire drug level reaches the outlet 604A (shown in phantom in FIG. 26B)of the device 604. At this point the filling process is completed. Itshould be noted that during the filling process, if the user stopspushing the vial 602 into the transfer system 600 the drug may draininto the cylinder 614. This is prevented by getting the friction forceshigher than the impedance of the tubing 610 to the drug flow. In thealternative, it is also possible to dispose a one-way valve at the endof the tubing 610. Once the drug delivery device 604 is filled with aliquid drug, it is disconnected from the transfer system 600. Anyresidual drug in the system 600 can stay protected, and the needle 616is retracted and as described earlier with respect to the needle lockingmechanisms is secured in the cover 606, and cannot be reexposed to causeharm or injury.

[0135] FIGS. 28A-28C are cutaway views of the operation of anotherpreferred embodiment of a drug delivery system 630, in particular of aposition independent injection system in accordance with the presentinvention. In this embodiment, the injection system 630 is positionindependent, that is the injector is not required to be in a verticalposition during the injection process. Referring to 28A, the drugdelivery system 630 includes a vial 632 containing the liquid drug 634.The liquid drug 634 flows through the spike 636 along a tube 644A into acavity 652. The spike includes two paths, one path 642 for deliveringpressurized air into vial 632 from chamber 641 and another path 644 todeliver the liquid drug to the user via a needle 664. The liquid drugexits from the path 644 and travels along tube 644A disposed at thebottom of the spike. A one-way valve 638 insures the unidirectional flowof the liquid drug 634 into the cavity 652A. Spring 640 holds piston 656within the cavity 652. A floating piston 650 moves in the cavity 652. Aseal 654 is included in the floating piston. Member 660 rests atop aneedle assembly 664A. Member 660 is hingedly connected to member 662.Member 662 has a finger 662A. Prior to use, the finger 662A rests withinan aperture 662B of the housing 660A. The notch 658 is the end of travelposition for the piston 656.

[0136] The path 642 from the air chamber 641 to the vial 102 pressurizesthe vial by delivering air thereto. The air chamber 641 is depleted ofair when the vial is moved downward. As the vial moves downward, amember 641A sealably slides within the walls of the chamber and forcesthe air into the vial. The member 641A is prevented from leaking air outof the chamber by the seal 641B.

[0137] In use, when vial 632 is pushed into the device 630, air from thecavity 641 enters into the vial 632 and pressurizes the liquid drug.This drug 634 under pressure flows via path 644 through the one-wayvalve 638 into the left side of the cavity 652. Pressurized air pushesthe floating piston 650 to the right side of the cavity 652. Thefloating piston 650 moves until the position of the notch 658, which isthe end of travel position for the piston 656 and thus for filling ofthe cavity 652. Thus, as illustrated in FIG. 28B, an accurate volume ofliquid drug is filled in cavity 652 and the device 630 is ready to beused.

[0138] As illustrated with respect to FIG. 28C, once the member 660 isdepressed, it causes the needle 664 to move downwardly outside thehousing-660A and into the user's tissue. Member 662 is hingedlyconnected to member 660. When 660 is depressed, it causes member 662 tomove upwardly disengaging the finger 662A from the aperture 662B andenables the spring 640 to return to a less compressed state. As it does,the spring 640 forces the piston towards the opposing end of the cavity652. This causes the liquid drug therein to move via channel 652A andneedle 664 into the user's tissue, the piston 656 is released due to themovement of member 662 in the upward direction. The piston 656 moves tothe left. The floating piston 650 is under pressure and moves the liquiddrug in cavity 652 through the injector needle 664 and into the user. Itshould be noted that after delivery of the liquid drug, the position ofthe floating piston 650 depends on the load on the spring 640. Toprevent the flow of residual drug under pressure, the spring 640continues to be in a preloaded state. The seal 654 is pushed to the leftside of the cavity 652 under pressure of spring 640 to seal against theexit of the pressurized residual drug via the channel 652A. Althoughdisclosed as having a pushing spring 640, other mechanisms may beincluded in the injector system to result in a position independentinjector.

[0139] Referring to FIG. 28D, a cutaway view of a spike 636 which bringsthe liquid drug 634 in fluid communication with the injector system isillustrated. The spike 636 penetrates the septum 639 of the vial 632when the vial is inserted into the cavity 640. The spike functions as apiston 641A and is sealably and slidably movable by means of the seal641B within the interior walls of the chamber 641. As describedhereinabove, the spike also consists of two paths, an air inlet 642 anda drug outlet 644. Once the vial 632 is inserted, pressurized air entersthe vial 632 from an air chamber 641 and forces the liquid drug 634 viaa flexible tube 644A to the injector system. The filling process for theinjector system in a preferred embodiment is preferably done under amaximum pressure gradient of 0.3 bar. This includes a margin forexample, priming at an altitude of 5,500 feet and is the maximumexpected back pressure.

[0140]FIGS. 29A and 29B illustrate partial cutaway views of anotherpreferred embodiment of the drug transfer system 670 in accordance withthe present invention. The drug vial 672 containing the liquid drug 674is inserted into a cavity 676. A spike 678 provides air into the liquiddrug vial 672 for pressurization of the drug 674 and additionally thespike provides for an outlet for the liquid drug to be delivered to adrug delivery system 680. The drug transfer system 670 is in fluidcommunication with the liquid drug vial 672 through a flexible tubing682 and a needle 684. A hydrophobic membrane 686 is disposed in theflexible tubing 682 to prevent the transfer of air into the drugdelivery system. This hydrophobic membrane 686 prevents back flow. Theair to pressurize the liquid drug 674 is provided by air in thereservoir 675. Further, a latch mechanism 688 secures the vial 672 tothe detachable delivery system 680 during a filling process.

[0141] Referring to FIGS. 29A-1, an enlarged view of the interfacebetween the drug transfer system 670 and the detachable drug deliverydevice 680 is illustrated. A hydrophobic membrane 692 is disposed at theinterface for blocking the flow of the drug once the drug deliverydevice 680 is filled. An elastomeric cover 694 is disposed around theneedle 684 for protection against the needle 684. Tab 693 is pulled offto remove the hydrophobic membrane 692 prior to use of the device 680.

[0142] In operation the liquid drug vial 672 is pressed into the cavity676 which causes the air in the reservoir 675 to be compressed and enterthe liquid drug vial 672. Air is prevented from leaking out of thecavity 675 by means of seal 685. The liquid drug 674 is pressurized anddelivered through the spike outlet 690. Residual air from the airreservoir 675 is vented from an opening in the latch mechanism 688 oncethe latch is disengaged from the drug delivery device at the end oftravel of the vial and subsequent end of the transfer process.

[0143] Referring to FIGS. 30A and 30B, the two piece 696, 697construction of the manifold in accordance with the present invention isillustrated. The manifold is a biocompatible material such as, forexample, polycarbonate or acrylic or pvc molding having a gasimpermeable membrane 698 welded in the part 696; The two pieces 696, 697are ultrasonically welded together.

[0144] Referring to FIGS. 31A-31E, perspective views illustrate analternate preferred embodiment of a drug delivery system 700 inaccordance with the present invention. This particular embodiment maybeused with the reconstituted drug delivery system and includes two vials702 and 704, a first containing a diluent and a second containing a drugthat needs to be reconstituted. In addition there is a pressurizingsystem, such as a built-in cylinder 706 in fluid communication with thediluent vial 702. The built-in pressurization system such as thecylinder 706, is disposed between the lyophilized drug vial and thediluent vial. A plunger 708 is slidably received into the cylinder 706to provide the necessary air pressure to effect drug transfer. Air ispushed into the diluent vial forcing the diluent from its vial into thelyophilized drug, compartment or vial 704. As discussed previously, ahydrophilic membrane is used as an air separator to minimize orpreferably prevent the entry of air into the user's tissue. In use, adiluent vial is inserted into the drug delivery system 700 followed bythe insertion of a drug vial. The plunger 708 is pushed downwards topressurize the air in the cylinder 706 and deliver it to the diluentvial 702. Once the diluent solution is pressurized it is delivered tothe drug vial 704 to reconstitute the drug. Pressing the knob mechanism710 displaces an injection needle which is used to inject thereconstituted drug into a user tissue. The depression of the knobmechanism and subsequent injection is similar to that described earlierwith regard to either the straight needle assembly shown in FIG. 18 orthe U-shaped needle shown in FIGS. 11, 13 through 17.

[0145] Referring to FIGS. 3F and 31G, two preferred embodiments 711, 713which provide a visual indication of device orientation are illustrated.The vertical indicators 711, 713 are shown as being disposed on the topof the plunger 708, however their location can vary to provideappropriate visual indication. In the first embodiment of the verticalindicator 711, a metal ball 714 rests upon a curved surface havingvisual indicators or scale 712 thereon. The ball 714 is enclosed withina clear casing 712A. The positioning of the ball 714 in the middle ofthe scale is an indication of vertical orientation. In the secondembodiment 713 of the vertical indicator, an air bubble 716 disposed ina liquid 718 enclosed within a clear housing 718A is used as the visualindicator of orientation with respect to the scale 719. The positioningof the air bubble 716 in the middle of the scale is an indication ofvertical orientation.

[0146] Referring to FIGS. 32A-32E, perspective views illustrate afurther alternate embodiment of the drug delivery system 720 inparticular a reconstitution and injection system, in accordance with thepresent invention. In this embodiment the reconstitution of the drugoccurs by the mixing of the diluent solution with the drug. A separatepressurization system for the diluent is not required for thisparticular embodiment and can only be used with low viscosity drugs. Inuse, the knob 730 is moved in a counter clockwise direction to begin thereconstitution process of the drug which opens a pathway connecting thediluent with the drug. The knob 730 is turned from a non-use position(as indicated when notches A and B align) to a ready to use position asindicated with the alignment of notches B and C. At this point, the knob730 may be depressed and the solution injected. The internal pressure ofthe diluent vial and gravity cause the diluent to transfer to the vialcontaining the drug. Further movement of the knob or dial 730 activatesan injection needle which interfaces with the user's tissue to deliverthe reconstituted drug. Again, the injection assembly is similar to theembodiments shown in FIGS. 11, 13-17.

[0147] Referring to FIGS. 33A-33I, cutaway views of preferredembodiments of the drug delivery system emphasizing the interlocksdisposed to provide for a safe system are illustrated. Referring inparticular to FIGS. 33A and 33B, the interlocks as required during shelflife of the drug delivery device 750 are illustrated. The end of thecylinder 752 has a biasing Lip 766 extending outward to matingly fitwith wall 758 and the lip must be flexible enough to bend with thepressure of wall 758 when vials are inserted in the assembly. Duringshelf life the cylinder 752 is secured by latch 754 and mating lip 756.This mating fit prevents the movement of the movable cylinder 752 in thevertical direction prior to use. As previously described, the cylinder752 provides pressurized air to the drug delivery system 750. Themovement in the downward direction of the cylinder 752 is minimized orpreferably prevented by holding the latches 754 and 756 on the wall 758.An upward movement of the cylinder 752 is prevented by latch 754.

[0148] Referring to FIG. 33C, the next step includes the insertion ofthe vials 760 and 762 into the device 750. Only after the insertion ofboth vials 760, 762 is the cylinder 752 free to be pushed in thevertical direction. The insertion of the vials forces the lip 766 inwardenabling it to clear the wall 758 and thus enable the cylinder 752 tomove downward. In addition, the latches 754 secure the vials in thedevice 750.

[0149] Referring to FIGS. 33D and 33E, the interlocks that play a roleonce the cylinder 752 is pushed as illustrated. The cylinder 752 ispushed downward until the end of travel position and is locked by themating of lip 766 and interlock element 768. Again, as described abovewith regard to pre-use, the lip 766 moves downward and catches onelement 768 and moves to a radially expanded position which prevents the115 cylinder from travelling upward again. A locking element 768 keepsthe cylinder in the bottomed out position. The element 768 is formed asapart of the wall 758.

[0150] In the area where the drug solution is injected there is apushing member that moves in a relative perpendicular fashion to thedirection of travel by the cylinder. A ball 772 is positioned prior touse within the housing to prevent depression of the member 776. When thecylinder is fully depressed, the lip 766, pushes a member 770 whichallows the ball 772 to drop into a groove 774 making the movement of thepushing member 776 possible only if the device is in a verticalorientation.

[0151] Referring to FIGS. 33F and 33G, during the injection processdifferent interlock elements insure the safe use of the drug deliverysystem. As the pushing member 776 is depressed, which is only allowed ifthe drug delivery system 750 is in a vertical orientation, the horns 778spread the latch 780 which allows the member 770 to press the ball 772in the upward direction. Note the pushing member 776 is already pushedto expose the needle 782.

[0152] Referring to FIGS. 33H and 33I, the interlocks during the phaseof disposing of the drug delivery device which follows the injectionphase axe illustrated. The pushing member 776 is released by the actionof the spring 777 pushing the member 776. Since the movement of the ball772 was limited by the body of the member 776, with the release of themember 776, the ball 772 can now move back into the groove 774 as it isassisted by the pressure applied by the rear shell latch 780. This locksthe pushing member 776 into position thereby preventing further use ofthe drug delivery device 750.

[0153] Referring to FIGS. 34A through 34D, a preferred embodiment of thedrug delivery device having an end of delivery indicator is illustrated.As discussed previously with respect to preferred embodiments of thedrug delivery system of the present invention, the drug delivery systemis activated by pressurized gas, for example, air. The air forces thedrug to the injection site by pressurizing the drug; A hydrophilicmembrane minimizes and preferably prevents the passage of air into theuser's body. The hydrophillic membrane is disposed in the drug path tothe user's tissue. Once wetted, the hydrophillic membrane allows liquiddrug to proceed into the user's tissue and stops the passage of air intothe user's tissue. In order to insure the effectiveness of the membrane,the hydrophillic membrane has to become wetted. To enhance theeffectivity of the drug delivery device, a hydrophobic membrane is alsopositioned in the drug path. Referring to the FIGS. 34A and 34B, aninlet 800 which provides the liquid drug 802 into a cavity 803 has botha hydrophobic membrane 806 and a hydrophillic membrane 810 disposedtherein. The hydrophobic membrane 806 allows air to pass, but stopsliquids. On the other side of the cavity 803 the hydrophillic membrane810 allows liquid drug to pass while stopping the flow of gas. At oneend of the hydrophobic membrane 806 a flexible elastomeric diaphragm isdisposed that acts as an indicator once filled with gas, for example,air. The membrane being flexible, once filled with air gives an externalindication for end of delivery. The presence of air occurs only once theliquid drug has been delivered. It should be noted that the hydrophillicmembrane 810 is disposed close to the injection site as it allows liquidto go through to the injection site minimizing or preventing the flow ofgas into the user's tissue. FIG. 34D illustrates a manifold structureutilizing the end of delivery indicator 804 built into the manifold. Theseptum 814 surrounds a cavity containing he liquid drug. The spikes 816and 818 interface with the elastomeric stoppers of vials containing adiluent and a medicament.

[0154]FIG. 35 graphically illustrates the delivery profile from a highvolume vial having no additional air pressure in the vial. The profileillustrates pressure (in millibars) versus time (in seconds). Theinitial pressure in the vial is in the order of about 300 millibarswhich decreases during the delivery process to approximately 0 millibarsat the end of delivery process. This is in contrast to the pressure in avial that initially contained approximately 3 milliliters of air asillustrated with respect to FIG. 33. As a result, there is no residualair pressure in the vial once delivery is complete. The delivery processspanned a time period of approximately 86.4 seconds.

[0155]FIG. 36 graphically illustrates delivery duration and deliverypressure with respect to an air volume in a vial. Three differentprofiles are illustrated with a first one 830 which is indicative of thepressure (in millibars) before delivery, a second profile 832 indicativeof the residual pressure of the delivery and a third profile 834 whichis indicative of delivering 0.95 ml of a liquid drug over a time span ofabout 8 seconds.

[0156]FIG. 37 is a graphical illustration of the delivery parameters forall injection of a liquid drug having no additional air in the vial. Asdelivery of the drug occurs, the pressurization within the liquid vialdecreases over the approximately 17 seconds of delivery. These curvesillustrate test results of the delivery process of approximately 1 gramof liquid drug using a single drug delivery device for the same timeperiod.

[0157]FIG. 38 illustrates test results showing the air pressure gradienton hydrophilic membranes used to minimize or preferably prevent theentry of gas for example, air into the user's tissue. The test resultsprove membrane safety to insure that the membrane can withstand thepressures in the order of 2,700 millibars for a time duration of aboutsix minutes.

[0158]FIG. 39 graphically illustrates the performance of a drug deliverydevice in accordance with the present invention. Three delivery profiles840, 842, 844 (in ml) vs. time (in seconds) are illustrated for areconstituted lyophilized drug delivery system. The system includes a0.45 micron pore size hydrophillic membrane to minimize or preferablyprevent the flow of gas into the user's tissue. This particular poresize of the membrane provides an adequate particle filter and alsoallows the shortest time to deliver the drug to the user's tissue.

[0159]FIG. 40 is a flow chart that describes the methods for delivery ofa lyophilized drug in accordance with the present invention. The methodsinclude the step 899 of inserting the drug and diluent containers intothe drug delivery device. Further per step 900, the method includesactivating a pressurized air source which in turn is followed by thestep 902 of pressurizing a diluent solution in a diluent vial. Asdiscussed with respect to FIGS. 19A-19F, the pressurizing cat beprovided by subsystems which include but are not limited to a compressedair supply, a chemical gas generator, a collapsible volume air supply, astandard syringe or cylinder.

[0160] The methods further include the step 904 of delivering thepressurized diluent solution to the lyophilized drug vial. Thelyophilized drug is reconstituted per step 906 as a result of the mixingof the diluent with the lyophilized drug. The methods further includethe step 908 of providing the liquid drug to an injector system ortransferring the liquid drug to a detachable delivery device. The liquiddrug is then injected into a user's tissue per step 910. The injectionneedle is then moved to a safe storage position per step 912.

[0161]FIG. 41 is a flow chart that describes the methods for deliveringa liquid medicament in accordance with the present invention. Themethods include the step 913 of inserting a drug container such as avial into the drug delivery system. Further, per step 914 the methodincludes activating a pressurized air source for low viscosity drugs. Itshould be noted that for drugs with a high level of viscosity nopressurization may be required. The method then includes the step 916 ofpressurizing the standard drug vial. The pressurized liquid drug istransferred to a drug delivery system such as an injector system, ordetachable delivery devices per step 918. The liquid drug is theninjected into the tissue of a user per step 920. The method furtherincludes the step 922 of retracting the injector into a safe storageposition.

[0162] It is further appreciated that the present invention may be usedto deliver a number of drugs. The term “drug” used herein includes butis not limited, to peptides or proteins (and mimetic thereof), antigens,vaccines, hormones, analgesics, anti-migraine agents, anti-coagulantagents, medications directed to the treatment of diseases and conditionsof the central nervous system, narcotic antagonists, immunosuppressants,agents used in the treatment of AIDS, chelating agents, anti-anginalagents, chemotherapy agents, sedatives, anti-neoplastics,prostaglandins, antidiuretic agents and DNA or DNA/RNA molecules tosupport gene therapy.

[0163] Typical drugs include peptides, proteins or hormones (or anymimetic or analogues or any thereof) such as insulin, calcitonin,calcitonin gene regulating protein, atrial natriuretic protein, colonystimulating factor, betaseron, erythropoietin (EPO), interferons such asα, β or γ interferon, somatropin, soinatotropin, somastostatin,insulin-like growth factor (somatomedins), luteinizing hormone releasinghormone (LHRH), tissue plasminogen activator (TPA), growth hormonereleasing hormone (GHRH), oxytocin, estradiol, growth hormones,leuprolide acetate, factor VIII, interleukins such as interleukin-2, andanalogues or antagonists thereof, such as IL-1ra; analgesics such asfentanyl, sufentanil, butorphanol, buprenorphine, levorphanol, morphine,hydromorphone, hydrocodone, oxymorphone, methadone, lidocaine,bupivacaine, diclofenac, naproxen, paverin, and analogues thereof;anti-migraine agents such as sumatriptan, ergot alkaloids, and analoguesthereof, anti-coagulant agents such as heparin, hirudin, and analoguesthereof; anti-emetic agents such as scopolamine, ondansetron,domperidone, metoclopramide, and analogues thereof; cardiovacularagents, anti-hypertensive agents and vasodilators such as diltiazem,clonidine, nifedipine, verapamil, isosorbide-5-monotritate, organicnitrates, agents used in treatment of heart disorders, and analoguesthereof, sedatives such as benzodiazepines, phenothiazines, andanalogues thereof; chelating agents such as defroxanune, and analoguesthereof; anti-diuretic agents such as desmopressin, vasopressin, andanalogues thereof; anti-anginal agents such as fluorouracil, bleomycin,and analogues thereof; anti-neoplastics such as fluorouracil, bleomycin,and analogues thereof; prostaglandins and analogues thereof; andchemotherapy agents such as vincristine, and analogues thereof,treatments for attention deficit disorder, methylphenidate, fluvoxamine,bisoprolol, tacrolimus, sacrolimus and cyclosporin.

[0164] While this invention has been particularly shown and describedwith references to preferred embodiments thereof, it will be understoodby those skilled in the art that various changes in form and details maybe made therein without departing from the spirit and scope of theinvention as defined by the appended claims. For example, some of thefeatures of the position independence can be used in connection withreconstitution combination systems, transfer systems or injectionsystems. Likewise interlock features may be used with any of theaforementioned systems.

What is claimed is:
 1. A liquid drug transfer system comprising: ahousing; a port in said housing that received a container; a deliverydevice that can be connected to the housing to receive a liquid from thecontainer; and an end of delivery indicator.
 2. The liquid drug transfersystem of claim 1 wherein said end of delivery indicator comprises adiaphragm.
 3. A liquid drug transfer system comprising: a housing; aport in said housing that received a container; a delivery device thatcan be connected to the housing to receive a liquid from the container;a pressurizing mechanism that pressurizes said container; and a lockingmechanism that prevents activation of said pressurizing mechanism beforesaid container is inserted in said port.
 4. A liquid drug transfersystem comprising: a housing; a port in said housing that received acontainer; a delivery device that can be connected to the housing toreceive a liquid from the container; a pressurizing mechanism thatpressurizes said container; and a locking mechanism to preventactivation of the pressurizing mechanism when said device is notvertically oriented.
 5. A liquid drug transfer system comprising: ahousing; a port in said housing that received a container; a deliverydevice that can be connected to the housing to receive a liquid from thecontainer; and wherein a predetermined volume of a liquid drug isdelivered using a penetrating member having an adjustable height thatpierces said container of liquid drug.
 6. The liquid drug transfersystem of claim 5 wherein said penetrating member comprises a spike thatis threadedly engaged with said housing.
 7. A liquid drug transfersystem comprising: a housing; a port in said housing that received acontainer; a delivery device that can be connected to the housing toreceive a liquid from the container; and a support surface on saidhousing such that a user can insert said container with one hand whilesaid housing is positioned with said support surface.
 8. A liquid drugtransfer system comprising: a housing; a port in said housing thatreceived a container; and a pen injector that can be connected to thehousing to receive a liquid from the container.
 9. A method fortransferring a liquid comprising: inserting a container in a housing;transferring a liquid in the container to a delivery device, saiddelivery device having a penetrating member; separating the deliverydevice from said housing; and providing an end of delivery indicator.10. The method of claim 9 wherein said step of transferring the liquidcomprises providing a syringe as said delivery device.
 11. The method ofclaim 9 wherein the step of providing an end of delivery indicatorcomprises using a diaphragm.
 12. A method for transferring a liquidcomprising: providing a port in a housing; providing a locking mechanismin said housing that prevents activation of a pressurizing mechanismbefore a container is inserted in said port; inserting said container insaid port of said housing; actuating said pressurizing mechanism thatpressurizes said container; transferring a liquid in said container to adelivery device, said delivery device having a penetrating member; andseparating the delivery device from said housing.
 13. A method fortransferring a liquid comprising: inserting a container in a housing;providing a locking mechanism to secure the container in said housing;transferring a liquid in the container to a delivery device, saiddelivery device having a penetrating member; and separating the deliverydevice from said housing.
 14. A method for transferring a liquidcomprising: inserting a container in a housing; actuating a pressurizingmechanism that pressurizes said container; transferring a liquid in thecontainer to a delivery device, said delivery device having apenetrating member; separating the delivery device from said housing;and wherein a locking mechanism is provided to prevent activation ofsaid pressurizing mechanism when said device is not vertically oriented.15. A method for transferring a liquid comprising: inserting a containerin a housing; transferring a predetermined volume of a liquid drug byadjusting the height of a penetrating member which pierces the containerof liquid drug into a drug delivery device; and, separating the deliverydevice from said housing.